“Overall, the take-home point is that it's a small study so far and the follow-up time is still short, but it is pretty exciting preliminary data,” said Dr. Courtney DiNardo about the combination of Tibsovo plus Venclexta – with or without Vidaza – in IDH1-mutated acute myeloid leukemia.
Researchers have found the combination of Tibsovo (ivosenidib) plus Venclexta (venetoclax) — with or without Vidaza (azacytidine) – to be safe and effective in the treatment of patients with IDH1-mutated acute myeloid leukemia (AML), according to the results of a recent trial presented at the 2020 ASCO Virtual Scientific Program.
In an interview with CancerNetwork®, CURE®’s sister publication, senior study author Dr. Courtney DiNardo, associate professor of leukemia at The University of Texas MD Anderson Cancer Center, went into greater detail about what prompted the study, what the results mean for patients and how this could impact the future of AML treatment.
CancerNetwork®: Can you explain what prompted this study?
DiNardo: Sure. H1 mutations happen in about, 6 to 15% or so of AML patients. So, it's a minority, but it's a sizable minority. And those patients tend to be older patients who are usually not appropriate or benefiting from standard intensive chemotherapy, so there's been a lot of interest over the past couple of years to find better, more tolerable and efficacious regimens for patients with IDH1-mutated AML.
There are approvals of the IDH1 inhibitor ivosidenib, and then there are approvals of azacytidine with venetoclax, which is kind of a separate more broad-scope AML treatment regimen that does also seem to show good response in IDH1 mutations. So, the question really was, when you have these different treatment options, is there a way to give either ivosidenib and venetoclax together? Those are two different oral therapies that could be a well-tolerated oral outpatient regimen. Or is there a way to kind of put all three together into a triplet regimen of azacytidine, venetoclax and ivosidenib to further improve on the outcomes we're seeing with the new therapies?
Can you briefly discuss the methods of how you conducted the study?
It's a phase one study and as of now, all of the patients enrolled have been at MD Anderson, although we are seeing nice responses and we're trying to expand the study to other sites. So, in the future, the patients will be enrolled at other sites, but for right now, single institution at MD Anderson and we are testing first the doublet so the IDH1 inhibitor, ivosidenib with venetoclax. And we're testing venetoclax at the dose of 400 (mg) and the dose of 800 (mg).
The reason we're doing that is because ivosidenib is a CYP-inducer, so there are drug interactions. And so, when you're giving ivosidenib, it tends to induce the metabolism of venetoclax, so you may actually need a higher dose of that. So, the first part of this study really is just determining that we have the right dose in combination.
There are those two different cohorts of the doublet and then we evaluate what we're calling the triplet regimen, where we add azacytidine in at the venetoclax levels of 400mg and 800mg. So right now, we finished cohort one and cohort two, which are those two different doublet doses. And we're now enrolling into the first of the triplet cohorts.
What were your primary findings that you presented at ASCO 2020?
There are a couple of different findings to go through. The first is that, as I mentioned already, there really are drug interactions. So, it just kind of raises that important point that when you have different approved therapies, it's important not to just assume you can put them all together and it'll be the same doses.
But the next point is that it really is a well-tolerated regimen. We know the anticipated side effects of azacytidine with venetoclax, which is some degree of myelosuppression and febrile neutropenia and the risk of IDH-inhibitors, which is differentiation syndrome. We saw some of the same safety signals, but nothing new or increased intensity than we would otherwise have expected to see. So, the overall safety was kind of expected for a relapsed AML population, which is the majority of who we enrolled.
And in terms of kind of the efficacy endpoints, of course, which is what everyone's always the most excited about, there are some questions out there in the literature and preclinical data that suggests that you actually shouldn't put these drugs together; that they may actually antagonizing themselves. And so, one of the first things we wanted to do was make sure that we were seeing efficacy, hopefully what we would see with the agents alone, but the goal is to see even better responses and thankfully, so far, we are.
The composite complete response rate in our 20 evaluable patients so far is about 80%, which is pretty dramatic in a population that's primarily relapsed/refractory secondary AML itself. And of those responding patients, half of them become MRD-negative by flow cytometry. So, a nice validated endpoint of a deep remission. And the median follow-up is relatively short in this study, only about seven or eight months. And the median overall survival hasn't been met, thankfully. All underlying disease types have responded. The particular population that I mentioned that were MRD-negative, the remission rate, those patients all continue on study, very durable responses and no progressions or relapses so far.
So overall, the take home point is that it's a small study so far and the follow-up time is still short, but it is pretty exciting preliminary data.
It sounds like there's an unmet need currently in this subgroup of patients. What does this patient population have to look forward to?
You know, it really is amazing. A couple of years ago, the treatment options for an older AML patient who wasn't a good candidate for the intensive chemotherapy was really palliative. At best we would give them azacytidine (or other drugs) with a goal to improve quality of life and hopefully achieve transfusion independence for a time, but we really weren't providing significantly durable responses.
I think things have just changed so rapidly and it's just such an exciting time to be a leukemia researcher because there are so many new effective treatments. And so, one of the joys of my job is trying to figure out how to take different effective therapies and put them together to make them even more effective for the benefit of our patients.